JP2659531B2 - Anti-bacterial composition - Google Patents

Abstract

The invention provides new synergistin derivatives of formula <IMAGE> (I) in which Y is hydrogen or dimethylamino and R is a 3- or 4-quinuclidinyl radical, the isomers thereof and their mixtures, and their salts, also the preparation thereof. These compounds may be made by reaction of the corresponding 5-methylene compounds with the appropriate mercaptoquinuclidine. The products of formula (I), optionally combined with pristinamycin IIA or a derivative of pristinamycin IIB of the formula <IMAGE> (II) are useful as antimicrobials.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to a synergistin derivative, a method for producing the same and a pharmaceutical composition containing the same.

European Patent Application No. 133,097 describes:
A substituted synerdistin derivative at the 5δ position with the advantage of solubility is described.

[0003] Pristinamycin and virginiamycin are known compounds: J. Preud'homm.
e) et al., Bull. Soc. Chim. Fr., 2 , 5,
85-91 (1968).

[0004] The present invention uses the formula

[0005]

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Wherein Y is hydrogen or dithimeramino, and R is 3- or 4-quinuclidinyl. formula
The compounds of (I) exist in isomeric forms, and these isomers and mixtures thereof also fall within the scope of the present invention.

According to a feature of the present invention, compounds of formula (I) wherein Y and R have the same meanings as defined above, can be prepared by reacting a thiol of the formula R--SH (II) wherein R is as defined above. ,formula

[0008]

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Wherein Y is as defined above.

The reaction is generally carried out in an organic solvent such as an alcohol (for example methanol), a ketone (for example acetone) or a chlorinated solvent (for example chloroform) or a mixture of such solvents, at from -78 ° C. to the reflux temperature of the reaction mixture. And preferably at a temperature of about 20 ° C.

When R represents 3-quinuclidinyl,
It can be seen that a thiol of the formula (II) in the (R) or (S) configuration gives the synerdistin derivative of the formula (I) in the corresponding configuration.

The thiol of formula (II) wherein R is 3-quinuclidinyl has the formula RS-COR '(IV) wherein R is as defined above and R' has 1 carbon atom.
~ 4 alkyl, preferably methyl] can be obtained by any known method of making thiols from thiol esters without affecting the rest of the molecule. The reaction is performed in an alkaline medium,
It is carried out by alcoholysis at a temperature of from 20 ° C. to the reflux temperature of the reaction medium in the presence of sodium methylate or sodium hydroxide in an alcohol such as methanol. Thiol esters of formula (IV) can be obtained from RP Volante, Tet. Leto.
t.), 22 (33), 3119 (1981), alcohols of formula R-OH (V) wherein R is as defined above and formula R'- CO-SH (VI) wherein R 'is as defined above, prepared by treatment with triphenylphosphine and a dialkyl azodicarboxylate such as diisopropyl azodicarboxylate. sell. The reaction is carried out under conditions similar to those described in the above references.

The alcohols of formula (V) in the (R) or (S) form give thiol esters of the general formula (IV) in the (S) or (R) configuration, respectively.

Alcohols of the general formula (V) in the (R) or (S) form are described by B. Ringdahl et al.
Suek (Acta. Pharm. Suec.), 16 , 281 (197)
It can be manufactured by the method described in 9).

The general formula (I) wherein R is 4-quinuclidinyl
Thiols of I) are described by A. Grob, Helv. Chim. Acta, 57 , 2339 (1974).
In the manner described in

The product of formula (III) may be prepared as described in European Patent Application No. 133,098.

When the product of formula (I) is in the form of a mixture of isomers, it is possible to separate the latter by any known method which does not adversely affect the molecule, for example by high performance liquid chromatography. It is.

The product of formula (I) can be purified by conventional methods, for example by crystallization, chromatography or continuous extraction in acetic acid and a basic medium. As is known in the art, synerdistin is sensitive to alkaline media, so a "basic medium" as used in this context is a medium in which the pH is just sufficient to liberate the raw material from the acid addition salt, i.e., pH.
Means not more than 7.5-8.

The product of formula (I) can be converted from an acid addition salt by the action of an acid in an organic solvent such as an alcohol, ketone, ester or chlorinated solvent. The salt precipitates, if appropriate, after concentrating the solution. This can be separated by filtration or gradient. Acid addition salts may also be obtained as aqueous solutions by adding an aqueous solution of the corresponding acid to the product of formula (I).

[0020] Synerdistin obtained by fermentation is
Gram-positive bacteria [eg Staphyolcoc
cus), Streptococcus, Pneumococcus (Pneumoco
ccus), or Enterococcus] and gram-negative bacteria [e.g., Haemophilus, gonococcus (Genoc).
There is a great need in medicine for the treatment of many conditions induced by O. occus or Meningococcus. However, such synerdistin has the disadvantage that it is insoluble in aqueous media and can only be administered orally, generally in the form of gelatin capsules, dragees or tablets. As a result of this insolubility, it is not possible to use the known synerdistin if the patient cannot swallow. This is especially the case in pediatric and respiratory patients, while in the environment where the active range of synerdistin is large, for example, Comatoses Septi.
caemia), it may be indicated as a useful drug.

The novel products according to the invention have the considerable advantage that they can be dissolved in water in therapeutically useful dosages as their salts while retaining the general activity range of synerdistin. They are especially Staphylococcus aureus (Staphylo
coccus aureus Smith) in vitro
It is active at a concentration of 5 μg / ml and in vivo at a dosage of 5-50 mg / kg subcutaneously in mice.

Furthermore, it is particularly useful because of its low toxicity. This LD ₅₀ is generally 1 when administered subcutaneously to mice.
Greater than 50 mg / kg.

The product according to the invention can furthermore be characterized in that it comprises pristinamycin II _A or a compound of the formula

[0024]

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When used in combination with a soluble derivative of pristimicin II _B , it exhibits a synergistic phenomenon. In the above formula (VII, R ₁ is 1) i) each having 1 to 5 carbon atoms
1-pyrrolidinyl, piperidino, 1-azetidinyl, 1-azepinyl, morpholino, thiomorpholino and 1-piperazinyl (optionally having 1 to
One or two alkylamino or dialkylamino groups which may form a saturated heterocyclic system selected from (optionally substituted with 5 alkyl); or ii) 2- or 3-pyrrolidinyl 2,2-, 3- or 4-piperidyl, 2- or 3-azetidinyl,
Or an alkylthio group having 1 to 5 carbon atoms substituted by a 2-, 3- or 4-azepinyl group; 2) a formula Het-S- (VIII) wherein Het is optionally an alkyl having 1 to 5 carbon atoms 3-pyrrolidinyl, 3- or 4-piperidyl, 3-azetidinyl or 3- or 4 which may be substituted
-Represents an azepinyl group]; 3) the alkyl moiety optionally together with the nitrogen atom to which they are attached, 1-pyrrolidinyl, piperidino, 1
Dialkyl which may form a saturated heterocyclic system selected from -azetidinyl, 1-azepinyl, morpholino, thiomorpholino and 1-piperazinyl (optionally substituted by alkyl having 1 to 5 carbon atoms) Amino group; or 4) Formula

[0026]

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Wherein R ₂ is (i) optionally containing one or more nitrogen, oxygen and other heteroatoms selected from sulfur in the sulfoxide or sulfone form and optionally substituted with alkyl. 4-7 which may be
Membered nitrogen-containing heterocyclic group; or (ii) cycloalkylamino having 2 to 4 carbon atoms and containing 3 to 6 ring atoms, and N-alkyl-N-cycloalkylamino, alkylamino, Dialkylamino or dialkylcarbamoyloxy (the alkyl part of the last two groups, optionally together with the nitrogen atom to which they are attached, optionally other members selected from nitrogen, oxygen and sulfur in the form of a sulfoxide or sulfone 4 containing a heteroatom and optionally substituted by alkyl
Or 7-membered saturated or unsaturated heterocyclic system), or optionally substituted with one or two groups selected from nitrogen, oxygen and sulfur in the form of sulfoxide or sulfone. One or two 4-7 containing one or two other heteroatoms selected
Membered nitrogen-containing heterocyclic group, wherein the heterocyclic group is optionally substituted with an alkyl group, and the heterocyclic group is attached to the molecular chain they carry through a carbon atom. A linked alkyl chain, wherein at least one of the substituents contained in the alkyl chain is a nitrogen-containing substituent capable of forming a salt or [(S) -1-methyl-2-piperidinyl)]
A methyl group, and n is 1 or 2, wherein said alkyl group is straight-chain or branched and contains 1 to 10 carbon atoms, respectively, unless otherwise specified.] Is shown.

Pristinamycin II of the general formula (VII)
_{The B} derivative can exist in isomeric forms. These isomeric forms and their mixtures can be advantageously combined with the products of the formula (I).

In formula (VII) 4), when R ₂ represents a heterocyclic group, this group may be, for example, 3-azetidinyl, 3-azetidinyl,
When R ₂ represents an alkyl group having a heterocyclic substituent, the heterocyclic group may be, for example, one or two of the above-mentioned groups, pyrrolidinyl, 3- or 4-piperidinyl or 3- or 4-azepinyl. -Azetidinyl, 2-pyrrolidinyl, 2-piperidyl, 2-azepinyl, piperazinyl,
May be 4-alkylpiperazinyl, quinolyl, isoquinolyl or imidazolyl; when R _{2 comprises} a dialkylamino or dialkylcarbamoyloxy group wherein the alkyl moiety together with the nitrogen atom to which they are attached form a heterocyclic system, The heterocyclic group is, for example, 1-azetidinyl, 1
-Pyrrolidinyl, piperidino, 1-azepinyl, morpholino, thiomorpholino in the sulfoxide or sulfone state, 1-piperazinyl, 4-alkyl-1-piperazinyl, N-alkyl-1-homopiperazinyl or 1-imidazolyl.

R ₁ is as defined above for 1), 2) and 3)
The product of (VII) is described in European Patent Application No. 135,410.
And can be prepared from pristinamycin II _A according to the method described in this patent application.

R ₁ is as defined above in formula (VII)
The product of the formula is

[0032]

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Wherein R ₂ is as described above, provided that R 2
_{When 2} contains a sulfur-containing heterocyclic system, the sulfur atom can be present in the sulfide, sulfoxide or sulfone form.] Can be prepared by oxidation of a salt or protected derivative of pristinamycin II _B.

The reaction is optionally carried out in an aqueous medium or in an organic solvent, preferably a chlorinated solvent (eg methylene chloride, 1,2-dichloroethane or chloroform) or an alcohol (eg methanol or tert-butanol) or a mixture of these solvents. This is generally achieved using an in situ manufactured oxidizing agent. The reaction is optionally performed under nitrogen.

Oxidizing agents suitable for obtaining the product of formula (VII) wherein n = 1 include organic peracids such as percarboxylic acids or persulfonic acids (eg peracetic acid, pertrifluoroacetic acid, succinic acid, perbenzoic acid) Acid, m-chloroperbenzoic acid, p-nitroperbenzoic acid, permaleic acid, monoperphthalic acid, periodate or p-toluene persulfonic acid) or inorganic peracids (e.g. periodate or persulfate) Can be mentioned.

If it is desired to obtain the product of the formula (VII) where n = 2, selenium dioxide and hydrogen peroxide can be applied to the salt of the compound of the formula (X) or, as described above, peracids, in particular The reaction can be advantageously performed by reacting trifluoroacetic acid or m-chloroperbenzoic acid.

When the pristinamycin II _B derivative of the formula (X) is used in the form of a salt, a salt formed with an organic or inorganic acid, preferably with trifluoroacetic acid, tartaric acid, acetic acid, benzoic acid or hydrochloric acid, is used. Is done.

When the compound of formula (X) is used in the form of a salt or a protected derivative, the reaction is advantageously carried out at a temperature of -40 to 50 ° C.

If one wishes to obtain a product of formula (VII) where n = 1, the pristinamycin II _B derivative of formula (X) is converted to -60 in the presence of an alkali metal bicarbonate (eg sodium bicarbonate). It is also advantageous to use a temperature of ４０40 ° C.

When R ₂ contains an alkylamino or cycloalkylamino substituent, it is also possible to use protected derivatives of the product of formula (X). The latter can be protected with any amine protector whose introduction and removal does not affect the rest of the molecule. Preference is given to using trifluoroacetyl groups. It can be removed after the reaction by treatment with an alkali metal bicarbonate (eg sodium bicarbonate or potassium bicarbonate) in an aqueous medium.

The product of formula (X) is prepared in a manner similar to that described in European Patent Application No. 135,410.
Wherein R ₂ -SH (XI) [wherein, R ₂ is described above and is synonymous] it can be prepared by the action of a thiol of the pristinamycin II _A.

The product of formula (VII) wherein n is 2 has
By oxidizing the product of the general formula (VII) This reaction can also be prepared starting from pristinamycin II _B of general formula (X) under conditions similar to those described above for obtaining the product of formula (VII) where n = 2.

The products of the general formula (XI) can be prepared according to the methods described in the examples or analogously, in particular according to the methods of the following references: G. FIG. Urqu Art
art) et al., Org. Synth, 21 , 36
(1941); I. Vogel, J.
J. Chem. Soc., 1822 (194)
8); JH Chapman and L.A. N. Owen, J. Chem Suk, 579 (195
0); R. Synder et al., J. Am.
J. Am. Chem. Soc., 69 , 2672.
(1947); D. Reynolds et al., J. Org. Chem. 26 , 5125.
(1961); W. Haeffele et al., Proc. Sci.
Toileto Goods Assoc.), 32 , 52 (1959);
H. Barrer et al., J. Org Kem, 2
7 , 641 (1962); H. Biel
J. Am Chem Suk, 77 , 2250 (19
55).

If appropriate, the isomers of the product of the formula (VII) can be separated by chromatography or by fast chromatography.

The synerdistin derivative according to the present invention is 0.1 to 10 μg / cc in a test tube and 10 to 200 mg / kg (subcutaneously) in a living body at 10 to 90%.
Shows a synergistic effect on the antibacterial effect of pristinamycin II _A on Staphylococcus aureus when combined in proportions of ９０90-10%.

For therapeutic use, the novel products according to the invention can be used as such, ie in the base state. However, for use in aqueous solutions, which is an important advantage of the products of the present invention, their pharmaceutically acceptable salts,
That is, preferably in combination with pristinamycin II _A ,
Alternatively, the formula (II) may be dissolved as a pharmaceutically acceptable salt per se or, if appropriate, as a base if the dissolution is sufficient to obtain a solution containing a product amount at least equal to the therapeutically active dosage. VII) Pristinamycin I
In combination with a soluble derivative of I _B, it is particularly advantageous to use non-toxic salts at the dosages used.

Pharmaceutically acceptable salts include addition salts of inorganic acids, such as hydrochlorides, hydrobromides, sulfates, nitrates,
Or phosphates or addition salts of organic acids such as acetates, propionates, succinates, maleates, fumarates, methanesulfonates, p-toluenesulfonates, isethionates, citrates , Adipates, lactopionates or substituted derivatives of these compounds.

The following example illustrates the practice of the present invention. The NMR spectra of the products shown in the examples and reference examples show general properties common to all products of the general formula (I) or (VII) and a unique characteristic for each of the products depending on the substituents. Exhibit special properties.

In the following examples, only the special properties due to the variable groups are mentioned. All protons are represented by the general formula (XII). J. O. Anteunis et al. [Eur.
J. Biochim.), 58 , 259 (1975)].

[0050]

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For the product of general formula (VII), all protons are designated according to the numbers shown below:

[0052]

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Except where otherwise noted, spectra were recorded at 250 MHz in deuterated chloroform. Chemical shifts are expressed in ppm relative to tetramethylsilane. The abbreviations used are as follows.

S = single line d = double line t = triple line m = multiple line c = complexity dd = double line double line dt = triple line double line ddd = double line double line Doublet dddd = Doublet doublet Doublet doublet It is understood that the different isomers are arbitrarily classified according to the chemical shifts observed by NMR.

The isomers A ₁ and A ₂ of the product of the general formula (XIII) in which R ₁ is a group R ₂ S (O) n (n = 1) are indicated by the isomers having the following characteristic values: relates: (-CH ₃ of s, 33) about 1.7; about 3.8 (s, 17 of _{-CH 2 -); <5 (} d, H 27) isomer a ₂ or> 5
(D, H ₂₇ ) isomer A ₁ ; about 5.50 (broad d, H
₁₃ ); about 6.20 (d, H ₁₁ ); about 6.6 (= N
H); 28 (s, H 20).

The designation of the isomers B ₁ and B ₂ of the product of the general formula (XIII) in which R ₁ is the radical R ₂ S (O) n (n = 2) relates to the isomers having the following characteristic values: : About 1.5 (s, 3
3 -CH ₃ in); about 3.7 and 3.9 (2d, 17 of -
CH ₂ —); about 4.8 (m, H ₁₇ ); <5 (d, H ₂₇ )
Isomer B ₂ or> 5 (d, H ₂₇ ) isomer B ₁ ; about 5.7
(Rimitsuteingu AB, H ₁₁ and H _10); about 7.7 (8
Roh -NH-); about _{7.8 ((s, H 20)} .

The designation of the isomer A of the product of formula (XIII) wherein R ₁ is other than R ₂ S (O) n is such that when 27 H is about 4.7 (d, J
< 1 Hz) except that R ₁ has the same NMR properties as described above for isomers A ₁ and A ₂ of the product of the general formula (XIII) in which the radical R ₂ S (O) n— About the body.

The designation of isomer B of the product of formula (XIII) wherein R ₁ is other than R ₂ S (O) n indicates that H at 27 is about 4.6 (d,
NMR identical to that described above for isomers B ₁ and B ₂ of the product of formula (XIII) except that J > 2.5H ₂ )
It relates to isomers that exhibit characteristic values.

In the following examples, flash chromatography relates to purification techniques, the characteristics of which are described in C. Still, M.E. Kahn and A.M. Mitra [Jei-Org-Kem, 43 ,
2923 (1978)], the use of silica having a particle size of 40 to 53 μm allows the use of silica at an appropriate pressure (50 kPa).

In the following examples, unless otherwise stated, all products can be dissolved in water at a concentration of at least 2% by weight as hydrochloride.

[0061]

【Example】

Example 1 Methanol (40 cc) and Kurorohoirumu mixture of (20cc) 5δ- methylene pristinamycin Maishi I _A (4.4
g) in a solution of 3-mercaptoquinuclidine (2.8 g)
Is added, and the resulting solution is heated at a temperature of about 20 ° C. for 4 hours.
Stir for 4 hours. Then, the reaction mixture was concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa). The residue obtained was suspended in ethyl ether (100 cc) and then filtered off. The resulting solid is washed with ethyl ether (3 × 10 cc) and then flash chromatographed [effluent: methylene chloride / methanol (90:10 by volume)].
The fractions were collected by 100 cc and purified. Fractions 11-15
And then concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa). The residue was stirred in ethyl ether (120cc). The solid obtained is filtered off and then flushed.
Collect 100 cc fractions by chromatography [effluent: methylene chloride / methanol (85:15 by volume)].
Purified again. Fractions 3-7 are combined and then at 30 ° C.
It concentrated and dried under reduced pressure (2.7 kPa). The residue was stirred in ethyl ether (50 cc), the resulting solid was filtered off, washed with ethyl ether (3 × 5 cc) and dried at 20 ° C. under reduced pressure (27 kPa). Thus, 5δ−
[(3-Quinuclidinyl) thiomethyl] pristinamycin I _A (1.7 g) was obtained in the form of a pale yellow solid with a melting point of about 200 ° C.

NMR spectrum Mixture of the four isomers 2.88 and 2.89 (2s, 4-N (CH ₃ ) ₂ ) 3.21 and 3.22 (2s, 4-CH ₃ ) 6.51 and 6 .53 (2d, 2-NH-) 6.57 and 6.58 (2d, 4ε) 7.28 and 7.85 (m, H of two abundant isomers
₆₎ 7.95 (m, two H ₆ amount less isomers) 8.78 and 8.81 (2d, 6-NH- two abundant isomer) 8.98 and 9.0 ( 2d, two minor isomers 6-NH-).

_A 5% aqueous solution of 5δ [(3-quinuclidinyl) thiomethyl] pristamycin IA was prepared in an amount sufficient to make 100 mg of the product 0.98 cc of 0.1 N hydrochloric acid 2 cc of distilled water.

3-Mercaptoquinuclidine could be prepared in the following manner: 3 in methanol (150 cc)
To a solution of-(acetylthio) quinuclidine (14.5 g) was added sodium methylate (0.5 g). The reaction mixture was heated under reflux for 1 hour. Sodium methylate (0.5 g) was added again, and the mixture was heated under reflux for 2 hours. This reaction mixture was concentrated to dryness at 40 ° C. under reduced pressure (2.7 kPa). Distilled water (40 cc) was added to the obtained residue, and then acetic acid (about 1 cc) was added to adjust the pH to around 8. The mixture was extracted with methylene chloride (3 × 20 cc). The combined organic phases are dried over sodium sulphate, filtered and then at 30 ° C. under reduced pressure (2.
7 kPa) under reduced pressure. The resulting brown oil was distilled under reduced pressure (920 Pa) and the fraction distilled at about 94 ° C. was collected. Thus, 3-mercaptoquinuclidine (2.8 g) was obtained.

3- (acetylthio) quinuclidine could be prepared in the following manner: tetrahydrofuran (3
Diisopropyl azodicarboxylate (31.6 cc) was added dropwise over 30 minutes to a solution of triphenylphosphine (42 g) in 00 cc) while maintaining the temperature at 5 ° C. under a nitrogen atmosphere. The resulting suspension was stirred at 5 ° C. for 30 minutes. To this suspension was added tetrahydrofuran (600 c
c) A solution of 3-hydroxyquinuclidine (10.2 g) and thioacetic acid (11.4 cc) in 3
Added over 0 minutes. The reaction mixture is then brought to 20 ° C.
Stirred at near temperature for 20 hours. Then, this is 40 ° C,
It concentrated and dried under reduced pressure (2.7 kPa). The obtained oil was dissolved in ethyl ether (400 cc), and then hydrochloric acid (3.
× 160 cc). The combined aqueous phases were washed with ethyl ether (100 cc) and neutralized to a pH of around 7 by addition of sodium bicarbonate. The pH of the resulting solution was then adjusted to about 9 with a few drops of a 10N aqueous sodium hydroxide solution. This mixture was methylene chloride (3 × 200 cc)
Extracted. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa). Thus, 3- (acetylamino)
Quinuclidine (14.7 g) was obtained in the form of a brown oil [R
f = 0.33; developing agent: methylene chloride / methanol (9
0:10 volume ratio)].

Example 2 Following a method similar to that described in Example 1, except that 5δ
- methylene pristinamycin I _A (6.15 g) and (3S)-3-mercaptoquinuclidine (1.1 g) as a starting material, and twice purified Fractions by 50cc in flash chromatography, [First flash chromatography: Eluent: methylene chloride / methanol (90:10 by volume), concentration of fractions 12 to 36 to dryness; Second flash chromatography:
Eluent: methylene chloride / methanol (90:10 by volume), fractions 3 to 20 are evaporated to dryness], 5δ- ｛[(3S)
3-quinuclidinyl] thiomethyl} to obtain a pristinamycin I _A (2.6 g) in the form of a pale yellow powder. This product could be obtained in crystalline form by the following method:
{[(3S) -3- quinuclidinyl] thiomethyl} pristinamycin I _A (2.6 g) in methanol (20c
Dissolved in c). A yellow solution was obtained. Filtration and 30 ° C,
After drying under reduced pressure (27 Pa), a scratch was used as priming water to precipitate crystals. 5δ-{[(3S) -3-quinuclidinyl] thiomethyl} pristinamycin I
_A (1.2 g) was obtained in the form of white crystals with a melting point of about 200 ° C. (The product crystallizes in combination with methanol).

NMR spectrum; one isomer (trace of isomer with respect to 5δ carbon) 0.62 (dd, J = 15 and 6, 1H, 5β ₂ ) 1.6-2.30 (m, 6H,

[0068]

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And 5δ) 2.4 (d, J = 15, 1H, 5β ₁ ) 2.5 to 2.75 (m, 5ε ₂ ,

[0070]

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1H and 1H of —CH ₂ S—) 2.9 to 3.20 (m, —S—CH ＝, —CH ₂ S— and

[0072]

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1H) 3.30 (m,

[0074]

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1H) 4.98 (dd, J = 14 and 7.5, 1H, 5ε ₁ ) 5.30 (m, 2H, 5α and 4α) 7.90 (dd, 1H, 1′H ₆ ) 5δ - {[(3S) -3- quinuclidinyl] thiomethyl} pristinamycin I _a could crystallized in the following way: 5δ - {[(3S) -3- quinuclidinyl] thiomethyl} pristinamycin I _a is ( 17.4 g) was dissolved in acetone (87 cc) previously refluxed. The resulting solution was filtered and the insoluble material was rinsed with acetone (10 cc). After 3 hours at 20 ° C., the resulting crystals are filtered,
Then it was dried. After recrystallizing the obtained product (14.8 g) in acetone (75 cc) under the same conditions, then after filtration and drying at 20 ° C. under reduced pressure (90 Pa), a melting point of about 185-190 ° C. White crystals (12.2
g) was obtained.

(3S) -3-Mercaptoquinuclidine could be prepared as follows: 10N aqueous sodium hydroxide solution (30 cc) in methanol (30 cc) maintained at about 25 ° C. (3S). It was slowly added to a solution of -3- (acetylthio) quinuclidine (2 g). The reaction mixture was stirred at a temperature around 20 ° C. for 2 hours. The pH of the reaction mixture was then brought to a value near 9 by the addition of acetic acid (about 10 cc). The resulting mixture was treated with methylene chloride (3
× 100 cc). The combined organic layers were dried over sodium sulfate, filtered, and 30 ° C. under reduced pressure (2.7
and concentrated to dryness under kPa). The obtained residue was depressurized (97
(0 Pa). In this way (3
S) -3-Mercaptoquinuclidine (12 g) was obtained in the form of white crystals with a melting point of 46 ° C. and a boiling point of 95 ° C./970 Pa. ^{_{(Α D 20 = -118 °,}} c = 1.1, methanol).

(3S) -3- (acetylthio) quinuclidine was obtained from triphenylphosphine (104.8 g), diisopropylazodicarboxylate (80.8 g) and (3R) -3-hydroxyquinuclidine (25.7).
Except that g) was used as a starting material, it could be prepared in the same manner as described in Example 1. (3S) -3- (acetylthio) quinuclidine (30 g) was obtained in the form of a yellow oil. [Rf = 0.2; effluent; methylene chloride / methanol (90:10 by volume)] RP Volante, Tet.
According to Leto, 22 (33), 3119 (1981),
The three carbons in the (R) configuration took over the (S) configuration during the reaction.

(3R) -3-hydroxyquinuclidine can be obtained from B.C. Ringdasahl, B.A. Lerusa (Re
sul) and D.I. Manufactured according to the method described by Dahlbom, Acta Pharma Suk, 16 , 281 (1979).

Example 3 Following a method similar to that described in Example 1, except that 5δ
- methylene pristinamycin I _A (6.15 g) and (3R)-3-mercaptoquinuclidine (1 g) as a starting material, after purification Fractions by 40cc in purification by flash chromatography [eluant: methylene chloride / methanol (85:15 volume ratio), and the concentrated to dryness fraction 20~30, 5δ - {[(3R ) -3- quinuclidinyl] thiomethyl} pristinamycin I _a (2
g) was obtained in the form of a beige powder. Melting point about 200 ° C.

NMR spectrum 0.58 (dd, J = 15 and 5.5, 1H, 5β ₂ ) 1.5-2.2 (c,

[0081]

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2.30 (c, 1H, 5δ) 2.35 (d, J = 15, 1H, 5β ₁ ) 2.50 (dd, 1H of —CH ₂ S—) 2.60 (dd, 1H, 5ε ₂ ) 2.78 (c,

[0083]

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1H) 2.90 to 3.10 (c, —CH ₂ S— and

[0085]

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1H) 3.15 (c, 1H)

[0087]

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3.48 (c,

[0089]

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1H) 4.95 (dd, 1H, 5ε ₁ ) 5.28 (c, 2H, 5α and 4α) 7.87 (c, 1H × 0.85, 1′H of the first isomer
₆ ) 7.93 (c, 1H × 0.15, 1′H of the second isomer
_{6) 5δ - {[(3R} ) -3- quinuclidinyl] thiomethyl} pristinamycin I _A could be recrystallized as follows: 5δ - {[(3R) -3- quinuclidinyl] thiomethyl} pristinamycin I _A (14.
15 g) was dissolved in methanol (75 cc). Distilled water (4 cc) was added to the solution and then allowed to crystallize at 4 ° C. The resulting crystals were filtered off and rinsed with a methanol / water (95: 5 by volume) mixture (4 × 10 cc).
After drying at 42 ° C. under reduced pressure (90 Pa), white crystals (10.22 g) were obtained. Melting point about 190 ° C.

(3R) -3-mercaptoquinuclidine is (3R) -3- (acetylthio) quinuclidine (32.
5 g) and a 10N aqueous solution of sodium hydroxide (35 cc) as starting materials, but could be prepared in a manner similar to that described in Example 2. (3R) -3-mercaptoquinuclidine (11.5 g) was prepared at a melting point of 45 ° C. and a boiling point of 9%.
Obtained in the form of white crystals at 0 ° C./830 Pa. (Α _D ²⁰ =
+ 121 °, c = 1.1, methanol).

(3R) -3- (acetylthio) quinuclidine was obtained from triphenylphosphine (104.8 g), diisopropylazodicarboxylate (80.8 g) and (3S) -3-hydroxyquinuclidine (25.7).
g) could be prepared by the method described in Example 1 except that g) was used as the starting material. There was thus obtained (3R) -3- (acetylthio) quinuclidine (33.8 g) in the form of a light brown oil. [Rf = 0.4; Eluent; methylene chloride / methanol (80:20 volume ratio)].

(3S) -3-hydroxyquinuclidine can be obtained from B.C. Ringdar et al., Acta Foram Suek,
16 , 281 (1979).

Example 4 Following the same procedure as described in Example 1, except that 5δ
- methylene pristinamycin I _A (3.5 g) and 4
-Starting with mercaptoquinuclidine (0.6 g) and concentrating to dryness, a solid was obtained, which was stirred in ethyl ether. After filtration, a solid in a solid color was separated, and fractions were collected and purified by flash chromatography in 50 cc portions [eluent: methylene chloride / methanol (85:15 by volume)]. The fractions 19 to 35 were concentrated to dryness, washed with ethyl ether, filtered, and the obtained solid was dried at 20 ° C. under reduced pressure (2.7 kPa) to give 5δ.
- [(4-quinuclidinyl) thiomethyl] pristinamycin I _A (1.2 g) is gray, mp about 200 ° C. were obtained in the form of Katsuta powder.

NMR spectrum (2 isomers at 5δ carbon, approximately 85:15 ratio): 0.62 (dd, J = 15 and 5.5, 1H, 5β ₂ ) 1.87 (t, 6H,

[0096]

Embedded image

2.20 (c, 1H, 5δ) 2.28 (c, 1H, —CH ₂ —S—) 2.35 (d, J = 15, 1H, 5β ₁ ) 2.47 (dd, 1H , 5ε ₂ ) 2.10 (t, 6H,

[0098]

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3.22 (dd, 1H, —CH ₂ —S—) 5.01 (dd, 1H, 5ε ₁ ) 5.29 (broad d, J = 5.5, 5α) 7.86 (c, 0.85H, 1 'of the major isomer
_{H 6) 7.92 (c, 0.15H} , 1 of abundant isomer '
H ₆ ) 4-Mercaptoquinuclidine is A.I. Grob,
Halv. Chim. Acta, 57 , 2
339 (1974).

Example 5 Example 1 except that starting materials were 5δ-methylenevirginiamycin S (1.2 g) and (3R) -3-mercaptoquinuclidine (0.21 g) in methanol (20 cc).
The method described in the above was followed. Fractions were collected and purified in 10 cc fractions by flash chromatography [Eluent: fraction 3
Up to 5 methylene chloride / methanol (95: 5 by volume),
Then methylene chloride / methanol (80:20 volume ratio)]. Fractions 47 to 55 were concentrated to dryness, dried at 30 ° C. under reduced pressure (2.7 kPa), and dried at 5δ-｛[(3R) -3.
[Quinclidinyl] thiomethyl} -virginiamycin S (0.6 g) was obtained in the form of a grayish powder with a melting point of about 185 ° C.

NMR spectrum (2 for 5δ-carbon)
One of the isomers, the ratio of about 80:20): 0.4 (dd, J = 15 and _{5.5,1H, 5β 2) 1.5~2.2 (c} , 5H,

[0102]

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2 (c, 1H,

[0104]

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2.34 (d, J = 15, 1H, 5β ₁ ) 2.52 (dd, 1H of —CH ₂ S—) 2.63 (dd, 1H, 5ε ₂ ) 2.78 (dd,

[0106]

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1H) 2.85 to 3.15 (c, —CH ₂ S— and

[0108]

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1H) 3.48 (c, 1H)

[0110]

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4.94 (dd, 1H, 5ε ₁ ) 5.27 (broad d, J = 5, 1H, 5α) 7.82 (dd, J = 4 and 1, 1′H of the first isomer)
₆ ) 7.9 (dd, J = 4 and 1, 1 'of the second isomer
H ₆₎ described in Example 6 in methanol (200cc) 5δ- methylene building Guinea mycin S a (1.1 g) and (3S)-3-mercaptoquinuclidine (0.19 g) in Example 1 except that the starting material I followed the way I did. Fractions were collected and purified by flash chromatography at 10 cc fractions [Eluent: methylene chloride / methanol (90:10 by volume) up to fraction 35]. Fractions 19 to 32 were concentrated to dryness, dried at 30 ° C. under reduced pressure (2.7 kPa), and dried at 5δ-｛[(3S) -3.
[Quinclidinyl] thiomethyl} -virginiamycin S (0.5 g) was obtained in the form of a pale yellowish powder having a melting point of about 109 ° C.

NMR spectrum (2 for 5δ-carbon)
One of the isomers, the ratio of about 85:15): 0.39 (dd, J = 15 and _{5,1H, 5β 2) 1.5~2.3 (c} , 5H,

[0113]

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2.11 (c, 1H,

[0115]

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2.34 (d, J = 15, 1H, 5β ₁ ) 2.52 (dd, 1H of —CH ₂ S—) 2.64 (dd, 1H, 5ε ₂ ) 2.66 (dd,

[0117]

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1H) 2.90 to 3.2 (c, 6H, —CH ₂ S— and

[0119]

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1H) 3.3 to 3.5 (c,

[0121]

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1H) 4.95 (dd, 1H, 5ε)₁5.27 (broad d, 1H, 5α) 7.80 (dd, J = 4 and 1, 1H × 0.85, first)
1'H of the isomer of₆7.90 (dd, J = 4 and 1, 1H × 0.15, second
1'H of the isomer of₆) Example 7 Starting from (3S) -3-mercaptoquinuclidine (1.62 g)
Example except stirring as a substance and at -20 ° C for 20 hours
According to the same method as described in 2 above, 30 ° C. and reduced pressure
(2.7 kPa) and concentrated to dryness, then beige yellow meringue
(11.4 g) in the form of diethyl ether
(100 cc), filtered and then the same solvent (3
× 20cc). This product is described in Example 2
Recrystallized in acetone as described above to give 5δ-{[(3S) -3-
[Quinuclidinyl] thiomethyl} -pristinamycin I
_A(6.6 g) are obtained in the form of white with a melting point of about 198-200 ° C.
Was. This characteristic value is identical to the product obtained in Example 2,
HPLC analysis revealed that it contained 3% of the minor isomer.
Was.

[0123] was dissolved in Example 8 Acetone (5 cc) of (3S)-3-mercaptoquinuclidine (0.18 g), a solution of acetone (20 cc) in 5δ- methylene pristinamycin I _A (1g) - 1 at 20 ° C
Added over time. After stirring at −20 ° C. for 18 hours, the reaction mixture was filtered and the solid was rinsed with acetone (3 × 2 cc). After drying in air, 5δ-{[(3S) -3-
Quinuclidinyl] thiomethyl} pristinamycin I
_A (0.66 g) was obtained in the form of white crystals, mp 190 ° C. This characteristic value is identical to the product obtained in Example 2,
Analysis by HPLC contained 3% of the minor 5δ-isomer.

[0124] The solution of Example 9 Acetone was dissolved in (5cc) (3S) -3- mercaptoquinuclidine a (0.16 g), acetone (15 cc) in 5δ- methylene pristinamycin I _A (1.22 g) To -78
C. and the resulting solution was stirred at -78.degree. C. for 24 hours under nitrogen. The reaction mixture was then brought to 30 ° C. and reduced pressure (2.7 k
Concentrate to dryness under Pa) and obtain 1.4 g of a cream-white solid containing 5% of the minor isomer analyzed by HPLC and having the same characteristic values as the product obtained in Example 2. Was.

Reference Example 1 26-[(2-Diisopropylaminoethyl) thio] pristinamycin II dissolved in dichloromethane (40 cc)
_B (Isomer A) (3.59 g) was added to trifluoroacetic acid (0.4 cc).
Was added at 0 ° C. under a nitrogen atmosphere, and 85% pure m-chloroperbenzoic acid (1.06 g) was added while maintaining the temperature at 0 ° C.
Was added. After stirring at 25 ° C. for 20 hours, the reaction mixture was treated with a saturated sodium hydrogen carbonate solution. The organic phase was decanted and the aqueous phase was washed with methylene chloride (3 × 100 cc). The organic phases were combined, dried over magnesium sulfate, filtered and then concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa) to give a yellow solid (4.2 g). The fractions were collected and purified by flash chromatography [eluent: chloroform / methanol (90:10 by volume)] in 20 cc fractions. Fractions 22 to 28 were combined, and 30 ° C. under reduced pressure (2.7).
Concentration to dryness under kPa) gave a pale yellow solid which was stirred in ethyl ether (10 cc). The resulting solid was filtered off and 26-[(2-diisopropylaminoethyl) sulfinyl] pristinamycin II _B (isomer A ₂ ) (0.62)
g) was obtained in the form of a yellow powder with a melting point of about 155 ° C.

NMR spectrum:

[0127]

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[0128] 1.76 (s, 33 of CH ₃₎ 2.75~3.15 (m, 15 of = CH _2, -H ₄ and

[0129]

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3.81 (s, 17 = CH ₂ ) 4.76 (d, -H27) 5.51 (d, -H13) 6.20 (d, -H11) 6.48 (c, 8 = NH) 8.13 (s, -H20) Fractions 35-45 are combined, 30 ° C and reduced pressure (2.7 kPa).
Concentrate to dryness below to give a pale yellow solid which was stirred in ethyl ether (15 cc). The solid obtained is filtered off and 2
6-[(2-diisopropylaminoethyl) sulfinyl]
Pristinamycin II _B (isomer A ₁ 80%, isomer A
₂ 20%) was obtained in the form of a pale yellow powder, mp about 145 ° C..

NMR spectrum (isomer A ₁ ): 1.72 (s, -CH _{3 of} 33) 2.70-3.15 (m, 15 = CH ₂ , -H ₄ ,

[0132]

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3.81 (s, 17 = CH ₂ ) 5.26 (d, -H27) 5.46 (d, -H13) 6.15 (d, -H11) 8.11 (s, -H20) ) 26-[(2-Diisopropylaminoethyl) thio] pristinamycin II _B could be prepared as follows.

2-Diisopropylaminoethanethiol (16 g) in dichloromethane (30 cc) was dissolved in pristinamycin II _A (52 g) in a mixture of dichloromethane (260 cc) and methanol (520 cc).
C. and added dropwise under a nitrogen atmosphere. Then the solution was -2
The mixture was stirred at 0 ° C for 20 hours and concentrated at 30 ° C under reduced pressure (2.7 kPa). The obtained solid was washed with ethyl ether (2 × 100
0 cc), filtered off and filtered with acetonitrile (100 cc).
Crystallized in c). The crystals were filtered off and then dried at 40 ° C. under reduced pressure (90 Pa). As a result, 26-[(2-diisopropylaminoethyl) thio] pristinamycin II
_B (isomer A) (33.6 g) was obtained in the form of white crystals with a melting point of about 122 ° C.

[0135] NMR Spectrum: 1~1.15 (m, -CH _3-isopropyl) (-CH ₃ of s, 33) 1.72 1.80~2.20 (m , -H25, -H29)

[0136]

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[0137] 3.40 (broad d, -H26) 4.74 (broad s, -H27) 6.32 (m, -NH 8) 8.15 (s, -H20) 2- diisopropylamino ethane thiol, Prepared according to the method of DD Reynolds, DL Fields and DL Jillson, J. Org Chem, 26 , 5125 (1961).

Reference Example 2 26-[(2-Diisopropylaminoethyl) thio] pristinamycin II dissolved in chloroform (300 cc)
_B (Isomer A) (10 g) was added with sodium bicarbonate (1.22 g). The mixture was cooled to -50 DEG C. and 98% pure m-chloroperbenzoic acid (2.98 g) dissolved in chloroform (100 cc) was added dropwise. The mixture was stirred at −50 ° C. for 2 hours and 15 minutes, and then treated with a saturated aqueous solution of sodium hydrogen carbonate. After stirring at 25 ° C. for 15 minutes, the mixture was decanted, and the aqueous phases were combined, dried over magnesium sulfate, filtered and then concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa) to give a white meringue. (10.62 g) was obtained. This was dissolved in ethyl acetate (400 cc) and then treated with 0.1N aqueous hydrochloric acid (140 cc). The pH of the aqueous solution was then adjusted to 4.2 by the addition of a pH 4.2 buffer (400 cc). The aqueous phase was decanted and the organic phase was adjusted to pH 4.
Washed with buffer 2 (400 cc). Combine the aqueous phases,
Washed with ethyl acetate (2 × 150 cc). After decanting, the aqueous phase was adjusted to pH 7-8 by addition of sodium bicarbonate and then washed with dichloromethane (3 × 300 cc).
The organic phases were combined and washed with a pH 7.5 buffer (2 × 200 cc). Wash the aqueous phase with dichloromethane (50 cc),
The organic phases are then combined, dried over magnesium sulfate,
Filtration and concentration to dryness at 30 ° C. under reduced pressure (2.7 kPa) gave a pale yellow solid (8.04 g). This is ethyl ether
(100 cc), filtered off, then reduced pressure at 40 ° C
(90 Pa). In this way, 26-[(2-
Diisopropylaminoethyl) sulfinyl] pristinamycin II _B (isomer A ₂ ) (7.5 g) was obtained in the form of a yellow powder with a melting point of about 158 ° C. This NMR characteristic value was the same as that of Reference Example 1.

Reference Example 3 According to a method similar to that described in Reference Example 1, except that
-[(2-diethylaminopropyl) thio] pristinamycin II _B (6.3 g), trifluoroacetic acid (0.72 cc) and
Starting from m-chloroperbenzoic acid (1.91 g), fractions were collected and purified by flash chromatography [eluent: chloroform / methanol (90:10 by volume)] in 60 cc fractions, followed by fraction 7 9 was concentrated to dryness under reduced pressure (kPa) at 30 ° C., and 26-[(2-diethylaminopropyl) sulfinyl] pristinamycin II _B (isomer A ₂ ) (0.99 g)
Was obtained in the form of a yellow powder with a melting point of about 150 ° C.

[0140] NMR _{Spectrum: 1.03~1.20 (m, -CH 2 -CH} (C H 3) N (CH 2
C H ₃₎ -CH _{3 2} and CH ₃ of 32) 1.76 (s, 33) 3.82 (s, 17 of _{= CH 2) 4.79 (c,} -H27) 5.53 (d, -H13) 6.20 (d, -H11) 6.42 (c, = NH of 8.1) 8.13 (s, -H20) Fractions 23 to 35 at 30C under reduced pressure (2.7 kPa). After concentration to dryness, 26-[(2-diethylaminopropyl) sulfinyl] pristinamycin II _B (isomer A ₁ ) (0.64
g) was obtained in the form of a beige-yellow powder with a melting point of about 160-170 ° C.

[0141] NMR spectrum: 1.14 (m, -N (CH 2 C H 3) 2)

[0142]

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[0143] 1.73 (s, 33 -CH ₃ in) 3.81 (Rimiteingu AB, 17 of _{= CH 2) 5.28 (d,} -H27) 5.43 (d, -H13) 6.15 ( d, -H11) 6.88 (c, = NH of 8.) 8.10 (s, -H20) 26-[(2-Diethylaminopropyl) thio] pristinamycin II _B can be prepared by the following method. Made: Following a method similar to that described in Example 1 of European Patent Application No. 135,410, except that pristinamycin I
Using I _A (3.15 g) and 2-diethylaminopropane thiol (1.8 g) as starting materials, flash chromatography [Eluent: methylene chloride / methanol (90:
After collecting and purifying 20 cc fractions at 10 volume ratio), fraction 3
5 was concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C.
6-[(2-Diethylaminopropyl) thio] pristinamycin II _A (1.4 g) was obtained in the form of a yellow powder with a melting point of about 160 ° C.

[0144] NMR spectrum: 1 (c, 9H:. -H32 + -N (CH 2 C H 3) 2)

[0145]

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3.30 (c, 1H: -H26) 4.70 (d, 1H: -H27) 8.12 (s, 1H: -H20) 2-Diethylaminopropanethiol can be produced by the following method. Worked up: 1- (S-isothioureido) -2-diethylaminopropane dihydrochloride (2 in distilled water (150 cc)
9.5 g) to a 10N aqueous solution of sodium hydroxide (25 c
c) was added. The mixture was brought to 100 ° C. for 1 hour, then cooled to 20 ° C., adjusted to pH 9 by addition of 12N aqueous hydrochloric acid (8 cc) and extracted with ethyl ether (3 × 100 cc). The ether phases were combined, dried over sodium carbonate, filtered and concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa). The mixture was purified by distillation. 2-Diethylamino-1-propanethiol (5.8 g) was obtained in the form of a colorless liquid [bp 78 ° C./2.7 kPa].

1- (S-isothioureido) -2-diethylaminopropane dihydrochloride was prepared as follows:
Thiourea in a solution of 1-chloro-2-diethylaminopropane hydrochloride (41 g) in dimethylformamide (200 cc)
(16.7 g) was added. This mixture is kept at 100 ° C. for 30 minutes.
And then cooled to 20 ° C. The white precipitate formed was collected by filtration and dimethylformamide (3 × 20 c
c) and then washed with ethyl ether (3 × 20 cc).
1- (S-Isothioureido) -2-diethylaminopropane dihydrochloride (29.6 g) was obtained in the form of white crystals, mp 247-249 ° C.

1-Chloro-2-diethylaminopropane hydrochloride was prepared in the following manner: 2-diethylaminopropanol hydrochloride (45.2 g) was added to thionyl chloride (100 cc) over 15 minutes, then the mixture was heated to 80 ° C. Heated. After stirring for 2 hours, excess thionyl chloride was distilled off and the residue was taken up in ethyl ether (200 cc). 1-
Chlor-2-diethylaminopropane hydrochloride crystallized. After filtration, white crystals (48.2 g) having a melting point of 112 ° C. were obtained.

2-Diethylaminopropanol hydrochloride could be prepared in the following manner: ethyl ether (3
30 cc) ethyl 2-diethylaminopropionate (66
g) was added to a suspension of lithium aluminum hydride (10.6 g) in ethyl ether (1 l) maintained at 20 ° C. under nitrogen.
Was added slowly. The reaction was kept at a temperature of 35 ° C. for 5 hours, then the temperature was reduced to 0 ° C. Then water (12.4
cc) 5N aqueous sodium hydroxide solution (9.1 cc) and water
(41.3 cc) was added dropwise at 0 ° C., the mixture was stirred for 30 minutes, then filtered on a glass filter and washed with ethyl ether. The ether phase is dried over potassium carbonate,
It was filtered and then concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa). A yellow liquid (43.8 g) was obtained, which was mixed with acetone (2
00 cc) and then a 4.5 N solution of hydrogen chloride gas in ethyl ether (78 cc) was added. 2-Diethylaminopropanol hydrochloride crystallized. After filtration, melting point 9
White crystals (45.2 g) were obtained at 7-100 ° C.

Ethyl 2-diethylaminopropionate was converted to Braun et al., Bailstein,
61 , 1425 (1928).

Reference Example 4 26-[(2-Diethylaminopropyl) thio] pristinamycin II _B (isomer A) (4 g>, 98% pure m-chloroperbenzoic acid (1.16 g) and solid carbonic acid Sodium hydrogen
The same procedure as described in Reference Example 2 was followed except that (1 g) was used as a starting material. Flash chromatography
Purification was performed using [eluent: chloroform / methanol (93: 7 by volume)], and fractions 21 to 48 of 25 cc fractions were concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa). (2-Diethylaminopropyl) sulfinyl] pristinamycin I
I _B (isomer A ₂₎ (2.69g), obtained in the form of a yellow powder having the identical characteristic values of the product obtained in Reference Example 3.

26-[(2-Diethylaminopropyl) thio] pristinamycin II _B (isomer A) is initiated by pristinamycin II _A (15 g) and 2-diethylaminopropanethiol (4.62 g) Except for this, it was produced by treating in the same manner as described in Reference Example 1. Purified by flash chromatography [eluent: chloroform / methanol (90:10 by volume)] and 30
At 27 ° C under reduced pressure (2.7 kPa).
2 was concentrated to dryness to give a yellow solid (12 g). This was stirred in ethyl ether (60 cc), filtered and dried. This result was compared with 26-[(2-diethylaminopropyl) thio] pristinamycin II _B (isomer A) (8.2 g).
Was obtained in the form of a pale yellow powder with a melting point of about 120 ° C.

NMR spectrum:

[0154]

Embedded image

Reference Example 5 26-[(1-Diethylamino-2-propyl) thio]
Pristinamycin II _B (isomer A) (4.58)
g), 98% pure m-chloroperbenzoic acid (1.29)
g) and solid sodium bicarbonate (1.14 g) were followed as in Reference Example 2 except starting from. Flash chromatography [Effluent:
Chloroform / methanol (97: 3 by volume)]
Purification was performed by collecting the fractions at 0 cc each, and fractions 59-77 and 79-97, respectively, were concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa) to give the next, fraction 79 ~ 97 to 26-[(1-diethylamino-2-
Propyl) sulfinyl] pristinamycin II
_B (first isomer) (1.47 g) was prepared at a melting point of about 132 ° C.
Obtained in the form of a pale yellow solid: NMR spectrum: 1.02 (t, ethyl-CH ₃ )

[0156]

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1.72 (-CH _{3 of} s, 33)

[0158]

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[0159] 2.77 (m, -H ₄₎ 2.87 and 3.09 (2dd, 15 of = CH ₂₎

[0160]

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[0161] _{3.72 (m, -H 26) 3.80} (s, 17 of = CH) 4.92 (m, -H 27) 5.43 (d, -H 13) 6.15 (d, -H ₁₁₎ 6.72 (dd, 8 of = NH) 8.06 (s, from -H ₂₀₎ and fraction 59-77, 26 - [(1-diethylamino-2-propyl) sulphinyl] pristinamycin II _B (second isomer) (1.07 g) mp 128
Was obtained in pale yellow solid form of ° C.: NMR Spectrum: 1.72 (s, 33 -CH _{3 in) 3.4 (m, -H 26)} 3.79 (s, 17 of CH ₂₎ 4. _{74 (m, -H 27) 5.48} (d, -H 13) 6.18 (d, -H 11) 6.80 (m, 8 of = NH) 8.09 (s, -H 20) 26 -[(1-Diethylamino-2-propyl) thio]
Pristinamycin II _B (isomer A) was prepared from pristinamycin II _A (13 g) and 1-diethylamino-2.
Prepared by treating in the same manner as in Example 1 except that propane thiol (4 g) is used as starting material. Purification by flash chromatography [Eluent: chloroform / methanol (90:10 volume ratio)]
Fractions 46 to 55 of each fraction were collected at 30 ° C. under reduced pressure (2.7
After concentration under kPa), a pale yellow solid (8 g) was obtained.
This was crystallized in acetonitrile (30 cc). After filtration and drying, 26-[(1-diethylamino-2-propyl) thio] pristinamycin II _B (isomer A)
(5.91 g) were obtained in the form of white crystals, mp 136 ° C.

[0162] NMR Spectrum: 0.9~1.10 (m, -N (CH 2 C H 3) 2)

[0163]

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1.72 (-CH _{3 of} s, 33)

[0165]

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[0166] _{2.76 (m, -H 4) 3} (m, -S-CH =) 2.9~3.1 (2dd, 15 of _{= CH 2) 3.52 (m,} -H 26) 3 .81 (s, 17 of _{= CH 2) 4.78 (m,} -H 27) 5.46 (d, -H 13) 6.14 (d, -H 11) 6.40 (m, 8 of = NH) 8.09 and 8.10 (2s, -H ₂₀₎ 1- diethylamino-2-propanethiol is R. T.
Wragg, J. Chem Sok (C), 2087
(1969).

Reference Example 6 26-{[(2R) -2-diethylaminobutyl] thio] pristinamycin II _B (isomer A) (1.7
g), sodium bicarbonate (0.50 g) and purity 98
% Of m-chloroperbenzoic acid (0.45 g) as starting material, following the same procedure as described in Reference Example 2. Purification by flash chromatography [eluent: ethyl acetate / methanol 85:15 by volume]] and fractions 35 to 58 at 30 ° C. under reduced pressure (2.7 kPa).
After concentrating to dryness, a white solid (1.1 g) was obtained. This was stirred in ethyl ether (30 cc). After filtration and drying, 26-{[(2R) -2-diethylaminobutylaminobutyl] sulfinyl} pristinamycin I
I _B (isomer A ₂ ) (0.95 g) was obtained in the form of a white solid with a melting point of about 126 ° C.

NMR spectrum:

[0169]

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[0170]

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1.78 (-CH _{3 of} s, 33)

[0172]

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2.93 and 3.14 (2dd, 15 = CH ₂ ) 3.31 (m, -H ₂₆ ) 3.84 (s, 17 = CH ₂ ) 4.84 (d, -H _{27 ) 5.51 (d, -H 13)} 6.19 (d, -H 11) 6.30 (dd, 8 of = NH) 8.15 (s, -H 20) 26 - {[(2R) - 2-Diethylaminobutyl] thio] pristinamycin II _B (isomer A) is obtained by starting from pristinamycin II _A (8 g) and (2R) -2-dimethylaminobutanethiol (2.3 g). It could be manufactured by the same process as described in Reference Example 1. Purification by flash chromatography [eluent: dichloromethane / methanol (90:10 by volume)] and concentration of fractions 36 to 55 at 30 ° C. under reduced pressure (2.7 kPa), followed by 26- ｛ [(2
R) -2-dimethylaminobutylaminobutyl] thio}
Pristinamycin II _B (isomer A) (3 g) was obtained in the form of a pale yellow solid with a melting point of about 120 ° C.

0.9 g of this product was acetonitrile (5
After crystallization in cc) and filtration, 26-｛[(2R)-
2-Dimethylaminobutylaminobutyl] thio-pristinamycin II _B (isomer A) (0.2 g) was obtained in the form of white crystals with a melting point of about 122 ° C.

NMR spectrum:

[0176]

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[0177]

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[0178] 1.72 (s, 33 -CH ₃ in) 2.30 (s, -N (CH 3) 2) 2.5~2.85 (m, -S-CH 2 -CH = and -
H ₄₎ 2.93 and 3.10 (2dd, 15 of = CH ₂₎ 3.34 (broad _{d, -H 26) 3.83 (s} , 17 of = CH ₂₎ 4.76 (broad s, - _{H 27) 5.48 (d, -H} 13) 6.14 (d, -H 11) 6.26 (= NH) 8.13 (s, -H 20 of dd, 8) (R) -2- Dimethylaminobutanethiol can be obtained from triphenylphosphine (52.4 g), diisopropylazodicarboxylate (40 cc), (R) -2-dimethylaminobutanol (12 g) and thiolacetic acid (15.
Prepared in a similar manner to that described in Reference Example 7 using 2 cc) as the starting material (in which case the intermediate thioester was directly hydrolyzed during chromatography on silica gel).

Flash chromatography [Eluent: dichloromethane (1000 cc), then dichloromethane / methanol (85:15 by volume; 2000 cc),
Then, 100 cc fractions were collected and purified with dichloromethane / methanol (80:20 volume ratio; 4000 cc)], and fractions 42 to 60 were concentrated and dried under reduced pressure to obtain a yellow oil (14 g). Purified by distillation. As a result, (R) -2-dimethylaminobutanethiol (2.
4 g) in the form of a colorless liquid [bp 70-75 ° C./4
kPa].

(R) -2-dimethylamino-1-butano
Is described in M.E. Wenghoefer et al., Jie
J. Heterocycl. Chem.
 ),7(6), 1407 (1970)
Manufactured in the same manner. Reference Example 7 26-{[(2S) -2-dimethylamino-3-phenylp
[Ropyl] thio} pristinamycin II_B(Isomer A) (2.
67 g), sodium bicarbonate (0.7 g) and 98% pure
Other than starting with m-chloroperbenzoic acid (0.7 g)
Proceed in the same manner as described in Example 2
Chromatography [Eluent: chloroform / methanol
(90:10 volume ratio)] and collect and purify 20 cc fractions.
Fractions 19 to 23 were concentrated at 30 ° C under reduced pressure (2.7 kPa).
Dry to give a pale yellow solid (1.3 g). This is ethyl
The mixture was stirred in a 50 liter (50 cc) filter, and filtered to obtain 26-{[(2S)-
2-dimethylamino-3-phenylpropyl] sulfoni
} Pristinamycin II_B(Isomer A_Two) (1.18g)
Obtained in the form of a pale yellow solid with a melting point of about 150 ° C.

NMR spectrum (400 MHz, CDC
l ₃ ): 1.73 (-CH _{3 of} s, 33)

[0182]

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[0183] _{2.44 (s, -N (CH 3} ) 2) 2.77 (m, -H 4) (= CH 2 of 2dd, 15) 2.89 and 3.1 3.18 (m, - H ₂₆₎ 3.82 (s, 17 of _{= CH 2) 4.68 (d,} -H 27) 5.51 (d, -H 13) 6.19 (d, -H 11) 6.50 (dd , 8 = NH) 7.18 (d, ortho phenyl H) 7.23 (t, phenyl para H) 7.31 (t, phenyl meta _{H) 8.13 (s, -H 20} ) 26 - {[(2S) -2- dimethylamino-3-phenylpropyl] sulfonyl} pristinamycin down II _B 1% aqueous solution of (isomer a ₂₎ was prepared using the following: product 30 mg 0 0.45 cc of 1N hydrochloric acid in an amount sufficient to make 3 cc of distilled water 26-{[(2S) -2-dimethylamino-3-phenylpropyl] thio} pristinamycin II _B (isomer A)
The preparation of the starting material was carried out in a manner similar to that described in Example 1, except that pristinamycin II _B (7.1
3g) and (S) -2-dimethylamino-3-phenylpropanethiol (2.65g) as starting materials. Flash chromatography [Effluent:
Ethyl acetate / methanol (80:20 volume ratio)]
The fractions were collected and purified by cc, and fractions 33 to 43 were collected at 30 ° C.
The mixture was concentrated to dryness under reduced pressure (2.7 kPa) with a light yellow solid (4.
6 g) were obtained. This was stirred in ethyl ether (50 cc), filtered and then dried at 45 ° C. under reduced pressure (90 Pa). As a result, 26-{[(2S) -2-dimethylamino-3
-Phenylpropyl] thio} pristinamycin II _B (isomer A) (3.6 g) was obtained in the form of a pale yellow powder with a melting point of about 110 ° C.

NMR spectrum: 1.69 (s, —CH ₃ ) 33 2.38 (s, —N (CH ₃ ) ₂ )

[0185]

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[0186] _{2.73 (m, -H 4) 2.89~3.10} (2dd, 15 of = CH ₂₎ 3.26 (broad _{d, -H 26) 3.81 (s} , 17 of = CH ₂₎ 4.68 (broad _{s, -H 27) 5.47 (d} , -H 13) 6.12 (d, -H 11) 6.27 (m, 8 of = NH) 7.18 (d, ortho phenyl H) 7.21 (t, phenyl para H) 7.30 (t, of phenyl meta _{H) 8.11 (s, -H 20} ) (S) -2- dimethylamino-3-phenyl Propanethiol could be prepared as follows: (S) -2-dimethylamino-3- dissolved in methanol (50 cc).
To phenylpropanethiol acetate (crude; 20 g) was added sodium methylate (0.2 g) under a nitrogen atmosphere,
The mixture was heated under reflux for 2 hours. Then mix 30
The solution was concentrated to dryness under reduced pressure (2.7 kPa) at ℃ to obtain a liquid, which was purified by distillation. (S) -2-dimethylamino-
3-Phenylpropanethiol (2.4 g) was obtained in the form of a colorless liquid [bp 95 DEG C./14 Pa]. This was used for the next reaction as it was.

(S) -2-Dimethylamino-3-phenylpropanethiol acetate was prepared by the following procedure: Triphenylphosphine (41.97 g) and tetrahydrofuran (310 cc) were added at 0 ° C. under a nitrogen atmosphere. Then, diisopropyl azodicarboxylate (31.5 cc) was added dropwise and the mixture was kept stirring at 0 ° C. for 30 minutes. To the resulting white suspension, a mixture of (S) -2-dimethylamino-3-phenylpropanol (15 g) and thiolacetic acid (11.44 cc) dissolved in tetrahydrofuran (160 cc) was added dropwise. Stir at 0 ° C for 1 hour, then at 25 ° C for 1 hour.
After stirring for 30 minutes, the mixture was cooled at 30 ° C. under reduced pressure (2.7 k
It was concentrated and dried under Pa). The obtained oil was treated with methanol (19
0 cc) and the precipitated white solid was filtered off and the filtrate was concentrated to dryness at 30 ° C under reduced pressure (2.7 kPa). The residue was then stirred with isopropyl ether (200 cc), the white solid precipitate was filtered off again and the filtrate was concentrated to a yellow oil.
(45 g) was obtained. This was purified by flash chromatography [eluent: dichloromethane / methanol (90:10 by volume)] by collecting 100 cc fractions.
Fractions 37-55 were concentrated and dried at 30 ° C. under reduced pressure (2.7 kPa), and (S) -2-dimethylamino-3-phenylpropanethiol acetate (10.4 g) was added to an orange-yellow oil ( In the form of triphenylphosphine oxide).

(S) -2-dimethylamino-3-phenylpropanol can be obtained from T.I. It was prepared in a manner similar to that described by Hayashi et al., J. Org Chem, 48 , 2195 (1983).

Reference Examples 8 to 26 The following products were prepared in a manner similar to that described in Reference Example 2:

[0190]

[Table 1]

[0191]

[Table 2]

Reference Example 27 26-{[(S) -1-methyl-2-pyrrolidinyl] methylthio} pristinamycin II _B (isomer A)
(7.8 g), trifluoroacetic acid (0.91 g) and m
-Flash chromatography [eluent: chloroform / methanol (90:10 by volume)] according to a method similar to that described in Reference Example 1 but using chloroperbenzoic acid (2.4 g) as starting material. Fractions of 60 cc each were collected, and fractions 26 to 36 were concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C to give 26-｛[(S) -1-methyl-2-
[Pyrrolidinyl] methylsulfinyl} pristinamycin II _B (isomer A ₂ ) (2.3 g) was obtained in the form of a pale yellow powder with a melting point of about 140 ° C.

NMR spectrum: 1.76 (s, -CH _{3 of} 33) 2.48 (s, = NCH ₃ ) 1.70-2.60 (m, -CH ₂₉ and 25 = CH ₂ and

[0194]

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2.75 to 3.25

[0196]

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3.82 (s, 17 = CH ₂ ) 4.81 (d, -H ₂₇ ) 5.52 (d, -H ₁₃ ) 6.20 (d, -H ₁₁ ) 6.42 (dd) , 8 = NH) 8.14 (s, -H 20) fractions 46-59 of 30 ° C., vacuum (2.7 kPa) after concentrating to dryness under, 26 - {[(S) -1- methyl [-2-pyrrolidinyl] methylsulfinyl} pristinamycin II _B (isomer A ₁ ) (1.1 g) was obtained in the form of a pale yellow powder having a melting point of about 148 ° C.

NMR spectrum: 1.73 (s, —CH _{3 of} 33) 1.70 to 2.50

[0199]

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2.41 (s, = N-CH ₃ ) 2.65 to 3.25 (m, 15 = CH ₂ , 4 -H,

[0201]

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3.82 (Limiting AB, = CH _{2 of} 17) 5.45 (d, -H ₁₃ ) 6.17 (d, -H ₁₁ ) 8.11 (s, -H ₂₀ ) 26-[( 1-Methyl-2-pyrrolidinyl) methylthio] pristinamycin II _B could be prepared by the following method: pristinamycin II _A (10.5 g)
And [(S) -1-methyl-2-pyrrolidinyl] methanethiol (3.14 g) as the starting material, following a method similar to that described in Example 1 of European Patent Application No. 135,410. Purification by flash chromatography [eluent: chloroform / methanol (90:10 by volume)] and fractions 20 to 35 were concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa) to give isomer A. (7.8
g) Obtained in the form of a yellow powder with a melting point of about 120 ° C.

[0203] NMR spectrum: 1.70 (s, 33 -CH ₃ in) 2.38 (s, = N- CH 3) 1.70~2.50 (m, -H 29, 25 of the = CH ₂ and

[0204]

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[0205] _{2.60~3.20 (m, -S-CH 2} -CH =) 3.82 (s, 17 of _{= CH 2) 4.73 (d,} -H 27) 5.45 (d, _{-H 13) 6.15 (d, -H} 11) 6.41 (dd, 8 of = NH) 8.11 (s, -H 20) crude was dissolved in distilled water (100cc) S - [(S ) -1-methyl-2-pyrrolidinylmethyl] isothiouranium 2
A 4N aqueous solution of sodium hydroxide (10 g) was added to the hydrochloride (25 g).
0 cc) and then the mixture is brought to 90 ° C. under a nitrogen atmosphere.
For 2 hours. The reaction mixture was cooled to 0 ° C.
Treated with 12N aqueous hydrochloric acid (25 cc) and then extracted with methylene chloride (2 × 200 cc). The organic phase is dried over sodium sulphate, filtered and then at 30 ° C. under reduced pressure (2.7
It concentrated and dried under kPa). Thus, [(S)-
1-methyl-2-pyrrolidinyl] methanethiol (5.
9 g) were obtained in the form of a pale yellow oil. This was used in the next reaction step without further purification.

Rf = 0.15; silica gel chromatography plate; developing solution: chloroform / methanol (90:10)
Capacity ratio).

[(S) dissolved in ethanol (50 cc)
To -1-methyl-2-pyrrolidinyl] chloromethane hydrochloride (11.9 g) was added thiourea (10.7 g), and the mixture was stirred under reflux for 48 hours. The mixture was concentrated to dryness at 40 ° C. under reduced pressure (2.7 kPa). The residue was taken in hot ethanol (100 cc) and then filtered through plant activated carbon. The filtrate was vacuumed at 40 ° C. (2.7 k
Concentration and drying under Pa) gave a pale yellow oil (25 g).
It consisted of S-[(S) -1-methyl-2-pyrrolidinylmethyl] isothiouronium dihydrochloride and excess thiourea. Rf = 0.1; silica gel chromatography plate; developing agent: chloroform / methanol (90:10 by volume).

[(S) -1-Methyl-2-pyrrolidinyl] chloromethane hydrochloride can be prepared according to the method described in T. Hayashi et al., J. Org. Chem., 28 , 2195 (1983). Was completed.

[0209] Reference Example 28 26 - [(1-methyl-4-pyrrolidinyl) thio] pristinamycin II _B (2.6 g), trifluoroacetic acid (0.3 g) and m- chloroperbenzoic acid (0.8 g) Chromatography [Effluent:
Chloroform / methanol (90:10 volume ratio)] to collect and purify 40 cc fractions.
Concentrate to dryness at 0 ° C. under reduced pressure (2.7 kPa) to dryness.
[(1-Methyl-4-piperidyl) sulfinyl] pristinamycin II _A (isomer A ₂ ) (0.33 g) was obtained in the form of a yellow powder with a melting point of about 170 ° C.

NMR spectrum: 1.76 (s, —CH _{3 of} 33) 2.2 to 3.00

[0211]

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2.32 (s, = N-CH ₃ ) 3.82 (s, CH _{2 at} 17) 4.85 (d, -H ₂₇ ) 5.50 (d, -H ₁₃ ) 6.19 ( _{d, -H 11) 6.37 (dd} , 8 of = NH) 8.15 (s, -H 20) 26 - [(1- methyl-4-piperidyl) thio] pristinamycin II _B the following method And pristinamycin II _A (3.15 g) and 1-
Similar to that described in Example 1 of European Patent Application No. 135,410 except that methyl-4-piperidinethiol (1.6 g) was the starting material and triethylamine (0.6 g) was added to the reaction mixture. Purify by flash chromatography [eluent: methylene chloride / methanol (92: 8 by volume)] according to the method and fraction 4
-20 was concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa) to give 26-[(1-methyl-4-piperidyl) thio] pristinamycin II _B (0.9 g) having a melting point of about 180 ° C.
In the form of a yellow powder.

NMR spectrum:

[0214]

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[0215]

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[0216]

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[0217] _{3.55 (c, 1H: -H 26} ) 4.62 (c, 1H: -H 27) 7.70 (c, 1H: -H 8) 8.10 (s, 1H: -H 20 1) 1-Methyl-4-piperidinethiol is H. Barrer and R.A. E. FIG. Lyle, J. Org Chem, 27 , 641 (1962).

Reference Example 29 26-[(2-Diethylaminoethyl) thio] pristinamycin II dissolved in methanol (60 cc)
_To 7.8 g of _B , trifluoroacetic acid (0.92 cc) was added at 0 ° C. under a nitrogen atmosphere. After 15 minutes at 0 ° C., the temperature is raised to 15 ° C. and then selenium dioxide (1.3
7g) was added. When all of the selenium dioxide had dissolved, a 30% aqueous hydrogen peroxide solution (7 cc) was slowly added at a temperature below 25 ° C. After stirring at 25 ° C. for 1 hour, the reaction mixture was cooled to 10 ° C., treated with saturated sodium bicarbonate solution (50 cc) and then methylene chloride (4 × 5
0 cc). The organic phases were combined, dried over magnesium sulfate and then concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa). The obtained yellow solid is washed with flash
Purification was performed by collecting 40 cc fractions by chromatography [eluent: chloroform / methanol (90:10 by volume)]. After fractions 31 to 38 were concentrated and dried at 30 ° C. under reduced pressure (2.7 kPa), a yellow solid was obtained. Use this for flash chromatography [Effluent:
Ethyl acetate / methanol (80:20 volume ratio)]
Fractions were collected by cc and purified. Fractions 27-33 were concentrated to dryness under reduced pressure to give a white solid which was stirred in ethyl ether (50 cc), separated by filtration and then filtered.
Dried at 0 ° C. under reduced pressure (90 pa). This result 26-
[(2-Diethylaminoethyl) sulfonyl] pristinamycin II _B (isomer A) was obtained in the form of a white solid with a melting point of 150 ° C.

NMR spectrum: 0.97 (d of -CH ₃ and ethyl of 30 and 31)
_{CH 3) 1.75 (s, 33} -CH 3 of)

[0220]

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[0221] _{3.00~3.40 (m, -SO 2 CH 2} CH 2 N =) 3.82 (s, 17 of _{= CH 2) 5.34 (d,} -H 13) 5.43 (d _{, -H 13) 6.16 (d,} -H 11) 6.54 (dd, 8 of = NH) 8.10 (s, -H 20) reference example 30 26 - [(2-diisopropylamino-ethyl) thio ] Pristinamycin II _B (isomer A) (6.86 g),
Trifluoroacetic acid (0.77 cc), selenium dioxide (1.
15 g) and a 30% aqueous hydrogen peroxide solution (6.33 cc). Fractions were collected and purified by flash chromatography [eluent: ethyl acetate / methanol (80:20 volume ratio)] in 40 cc increments, and fractions 28 to 31 were concentrated at 30 ° C. under reduced pressure (2.9 kPa). After drying, a yellow solid (0.7 g) was obtained. This was subjected to flash chromatography [eluent: ethyl acetate / methanol (85:15).
Fractions were collected at 30 cc each and purified. Fraction 2
6-33 was concentrated to dryness under reduced pressure to give a yellow solid which was stirred in ethyl ether (30 cc), filtered off and then dried at 30 ° C. under reduced pressure. 26-[(2-Diisopropylaminoethyl) sulfonyl] pristinamycin II _B (isomer A) (0.6 g) was obtained in the form of a pale yellow solid with a melting point of 160 ° C.

NMR spectra: 1.06 (d, CH ₃ isopropyl) 1.75 (s, —CH _{3 of} 33) 2.79 (m, —H ₄ ) 2.92 and 3.10 (2dd, 15 = CH ₂₎ 2.7~3.30

[0223]

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3.52 (broad d, -H ₂₆ ) 3.82 (s, = CH _{2 of} 17) 5.27 (sharp d, -H ₂₇ ) 5.47 (d, -H ₁₃ ) 6.17 _{(d, -H 11) 6.42 (} m, 8 of = NH) 8.12 (s, -H 20) the present invention, in the form of free base or pharmaceutically addition salts of acceptable acids The product of formula (I) can be prepared by (1) one or more diluents or auxiliaries which are compatible with it and pharmaceutically acceptable, or (2) pristinamycin II _A or preferably Pristinamycin I of the general formula (VII)
Soluble derivatives of I _B, also provides a pharmaceutical composition comprising in combination with any of the. The pharmaceutical composition according to the present invention can be used parenterally, orally, rectally or topically and may contain other bioactive ingredients if desired.

The sterile compositions for parenteral administration are preferably aqueous or non-aqueous solutions or suspensions or emulsions. Solvents or excipients include water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters such as ethyl oleate,
Alternatively, other suitable organic solvents can be used. These compositions may contain additives, in particular wetting agents, fluid pressure regulators, emulsifiers, dispersants and stabilizers. The disinfection can be effected in several ways, for example by aseptic filtration, by incorporation of the disinfectant into the composition, by irradiation or by heating. They can also be manufactured in sterile injectable media and in the form of sterile solid products which can be dissolved at the time of use.

Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

As solid compositions for oral administration, tablets, pills, powders or granules can be used. In these compositions, the active product according to the invention (combination with other pharmaceutically compatible products, if appropriate) is combined with one or more diluents or additives such as sugar, lactose, or Mix with starch. These compositions may also contain substances other than diluents, for example, lubricating agents such as magnesium stearate.

As liquid compositions for oral administration, pharmaceutically acceptable emulsions, suspensions, syrups, and elixirs can be used including water or inert diluents such as liquid paraffin. . These compositions may also contain substances other than diluents, for example wetting, sweetening or flavoring agents.

Compositions for topical administration may be, for example, creams, ointments, lotions, ophthalmic lotions, mouth washes, nasal drops or aerosols.

In the treatment of humans, the products according to the invention are particularly useful for treating infections of bacterial origin. The dosage will depend on the intended effect and source of treatment. For adults, it is generally between 2000 and 4000 mg / day when given parenterally, especially by intravenous or gentle perfusion.

In general, a physician will be able to determine the most appropriate dosage depending upon age, weight, and all other factors specific to the subject being treated.

The following examples illustrate the compositions of the present invention.

Example A A reflux injection solution containing 5 g / l of the active product and having the following composition was prepared according to the usual techniques: 5δ-[(3S) -3-quinuclidinyl] thiomethyl— the injectable solutions for reflux pristinamycin I _a 5 g amount sufficient examples to the 0.1N hydrochloric acid aqueous 49cc of distilled water 1000 cc B active ingredient 1 g / l containing and having the following composition in conventional techniques accordance connexion prepared: 5δ - [(3S) -3- quinuclidinyl] thiomethyl - pristinamycin I _A 0.4g 26 - [(2- diethylaminoethyl) sulphonyl] - pristinamycin II _B, isomer A 0.6 g injection solvent for reflux and containing an amount example C active ingredient 1 g / ml sufficient to 0.1N aqueous hydrochloric acid solution 12.6cc of distilled water 1000ml having the following composition The Supporting connexion was prepared conventional techniques: 5δ - [(3S) -3- quinuclidinyl] thiomethyl - pristinamycin I _A 0.4g 26 - [(2- diisopropylamino-ethyl) sulfonyl] - pristinamycin II _B Isomer A 0.6 g 0.1N aqueous hydrochloric acid 12.3 cc amount sufficient to make 1000 ml of distilled water Example D An injection solution for reflux containing 1 g / l of the active ingredient and having the following composition is usually prepared. accordance connexion was prepared techniques: 5δ- [3- quinuclidinyl] thiomethyl - pristinamycin I _a 0.4g 26 - [(2- diethylaminoethyl) sulphinyl] - pristinamycin II _B, isomer a 0.6 g 0 1N aqueous hydrochloric acid solution 12.7 cc Amount sufficient to make up to 1000 ml of distilled water The bacteriostatic activity of the compounds of the invention is shown in the following test.

In vitro bacteriostatic activity against Staphylococcus aureus
Sex known amount (20 cm ³⁾ of a suitable culture medium - a series of media containing the Miyura tips (Muller-Hinto) agar], 1/10 of the volume, geometric series (the ratio of the compound to be tested = 2) A series of dilutions were added. This medium is placed at 37 ° C.
And inoculated with a multipoint inoculator giving trypsinized soybean juice diluted 1/100 in the same medium to give spots containing 10 ⁴ colony forming units of the microorganism. After inoculation, the medium was cultured at 37 ° C. for 24 hours. The minimum inhibitory concentration (MIC) of a test compound is the lowest concentration at which growth of a microorganism is inhibited.

For intraperitoneal infection of mice with Staphylococcus aureus
Appropriately diluted with 5% hog mucin against "Drain Heart Infusion"
Mice were injected intraperitoneally with 0.5 cm ³ of an 18-hour culture of the test microorganism in a suitably shaken medium (Difco). This inoculum kills control animals in 24-48 hours. The test compound was administered subcutaneously twice a day at the time of inoculation at 5 hour intervals, the first time one hour after the inoculation of the microorganism. A unit dose contained in a volume of 50 cm ³ / kg was used. The 50% cure dose (CD ₅₀ ) is the dose of a test compound at which the animal treated at the dose of the compound survives during the test period (8 days).

The following results were obtained.

[0237]

[Table 3]

Claims (1)

(57) [Claims] (1) Formula (1) Wherein Y is hydrogen or dimethylamino;
Is 3- or 4-quinuclidinyl], wherein at least one of synerdistin or a pharmaceutically acceptable salt thereof in the form of an isomer or a mixture thereof is converted to pristinamycin II _A or a compound of the formula ] In combination with a soluble derivative of pristymycin II _B of the formula above, wherein R ₁ is 1) i) each having an alkyl moiety of 1 to 5 carbon atoms optionally together with their attached nitrogen atom Forming a saturated heterocyclic system selected from pyrrolidinyl, piperidino, 1-azetidinyl, 1-azepinyl, morpholino, thiomorpholino and 1-piperazinyl (optionally substituted by alkyl having 1 to 5 carbon atoms); One or two alkylamino or dialkylamino groups which may be; or ii) 2- or 3-pyrrolidinyl, 2-, 3- or 4-piperidyl, 2- or 3-azetidinyl or 2-, 3- or An alkylthio group having 1 to 5 carbon atoms substituted by a 4-azepinyl group; 2) a compound of the formula Het-S- It may be substituted by the number 1-5 alkyl, 3-pyrrolidinyl, 3- or 4-piperidyl, 3- azetidinyl or 3 or 4
3) an alkyl moiety, optionally together with the nitrogen atom to which they are attached, 1-pyrrolidinyl, piperidino, 1
-Azetidinyl, 1-azepinyl, morpholino, thiomorpholino and 1-piperazinyl (optionally substituted with alkyl having 1 to 5 carbon atoms), dialkyl which may form a saturated heterocyclic system An amino group; or 4) a formula Wherein R ₂ contains one or more nitrogen, oxygen and another heteroatom selected from sulfur in the sulfoxide or sulfone form and is optionally substituted with alkyl. A 7-membered nitrogen-containing heterocyclic group; or phenyl, having 2 to 4 carbon atoms;
Cycloalkylamino and N-alkyl-N-cycloalkylamino, alkylamino containing up to 6 ring atoms,
Dialkylamino or dialkylcarbamoyloxy (the alkyl part of the last two groups, optionally together with their attached nitrogen atom,
Forming a 4 to 7 membered saturated or unsaturated heterocyclic system containing oxygen and another heteroatom selected from sulfur in the sulfoxide or sulfone form and optionally substituted by alkyl; Or one or two containing, optionally, one or two other heteroatoms selected from nitrogen, oxygen and sulfur in the form of sulfoxide or sulfone. Substituted with two 4- to 7-membered nitrogen-containing heterocyclic groups, wherein the heterocyclic groups may be optionally substituted with alkyl, and the heterocyclic groups may be substituted via a carbon atom. An alkyl chain attached to a molecular chain having at least one of the following substituents, provided that at least one of the substituents contained in the alkyl chain is a nitrogen-containing substituent capable of forming a salt or [(S)-
1-methyl-2-pyrrolidinyl] methyl group, and n is 1 or 2, and the alkyl group is linear or branched, and unless otherwise specified, 1 to 10 An antibacterial composition wherein the pristinamycin is, where appropriate, in the form of an isomer or a mixture thereof and optionally in the form of an acid addition salt.